Protein kinase C (PKC) is a family of calcium stimulatable and phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation, and differentiation. Protein kinase C is also fundamental to the processes involved in tumorigenicity, since it is the major high-affinity receptor for several classes of tumor promoters as well as for endogenous cellular diacylglycerols. These tumor promoters also stimulate protein kinase C catalysis. Castagna et al. (1982) J. Biol. Chem. 257:7847 reported direct activation of protein kinase C by tumor-promoting phorbol esters. The mechanisms of protein kinase C action have been described in U.S. Pat. No. 4,816,450 issued Mar. 28, 1989 to Bell et al., the disclosures of which are specifically incorporated as if fully set forth herein. Protein kinase C is activated by diacylglycerol (DAG), a neutral lipid, and when activated will transfer the .gamma.-phosphate of MgATP to a serine or threonine residue on a substrate protein.
Since the activation of protein kinase C has been implicated in several human disease processes, including cancer tumors, inflammation, and reperfusion injury, inhibition of protein kinase C should be of great therapeutic value in treating these conditions.
Protein kinase C inhibitors have been reported to potentiate the antitumor activity of cis-platin both in vitro and in vivo (Grunicke et al. (1989) Adv. Enzyme Regul. 28:201; and German Offenlegungsschrift DE 3827974). In addition, it has been suggested that protein kinase C would be a potential target for therapeutic design because of its central role in cell growth (Tritton, T. R. and Hickman, J. A. Cancer Cells 2:95-102 (1990)).
Protein kinase C inhibitors have been demonstrated to block platelet aggregation and release of neutrophil activating agents such as platelet activating factor (PAF)(Schachtele et al. (1988) Biochem. Biophy. Res. Commun. 151:542; Hannun et al. (1987) J. Biol. Chem. 262:13620; Yamada et al. (1988) Biochem. Pharmacol. 37:1161). Protein kinase C inhibitors have also been shown to inhibit neutrophil activation, and chemotactic migration (McIntyre et al. (1987) J. Biol Chem. 262:15730; Lambreth et al. (1988) J. Biol. Chem. 263:3818; Pittet et al. (1987) J. Biol. Chem. 262:10072; and Gaudry et al. (1988) Immunology 63:715), as neutrophil degranulation and release of proteolytic enzymes and reactive oxygen intermediates (Wilson et al. (1986) J. Biol. Chem. 261:12616; Fujita et al. (1986) Biochem. Pharmacol. 35:4555; Berkow et al. (1987) J. Leukoc., Biol. 41:441; Salzer et al. (1987) Biochem. Biophys. Res. Commun. 148:747; Kramer et al. (1989) J. Biol. Chem. 262:5876; and Dewald et al. (1989) Biochem. J. 264:879). Thus inhibitors of protein kinase C have the capability of blocking all three of the most significant mechanisms of pathogenesis associated with myocardial reperfusion injury, and should thus have a decided therapeutic advantage. Additionally, the inhibitory effect of protein kinase C inhibitors on keratinocytes, and on the oxidative burst in neutrophils will lead to an anti-inflammatory effect.
N-[3-(dimethylamino)propyl] alkylamides have been reported as components in hairspray, hair conditioner, asphalt, emulsifiers, bactericides, waterproofing materials and stabilizers (GB 2220216 A1; U.S. Pat. No. 4,874,604; JP 01103663 A2; De Groot et al. (1988) Contact Dermatitis 19(4):289; Khim-Farm. Zh. 15(2) 28, 1981, JP 53035915, DE 2646199, Seifen, Oele, Fette, Wachse, 102 (7) 181, 1976, DE 2249471, JP 47042486 and EPO 402, 266).
Since the activation of protein kinase C has been implicated in several human disease processes, including cancer tumors, inflammation, and reperfusion injury, inhibition of protein kinase C should be of great value in treating these conditions. Consequently there is a need for novel protein kinase C inhibitors. Further, protein kinase C inhibitors that are relatively specific for inhibition of protein kinase C and which have minimal effects on other metabolic pathways such as those associated with stimulation of protein kinase C by cAMP are greatly desired. Inflammation and reperfusion injury, particularly pertaining to cardiac injury, are common conditions for which there exists no definitive treatment despite extensive research and appropriate treatments for these conditions are needed.